In this specification, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not to be taken as an admission that the document, act or item of knowledge or any combination thereof was at the priority date:
(a) part of common general knowledge; or
(b) known to be relevant to an attempt to solve any problem with which this specification is concerned.
Whilst the following discussion concerns tocopherol and dermal therapy, it is also to be understood that the same principles apply to any application in which a therapeutic formulation containing electron transfer agents may be used.
The skin is the largest organ of the body, and, among other things, functions to protect the internal organs from external chemical, physical and pathological hazards. Normal skin is composed of an outer epidermis covering sub dermal layers, where each layer comprises different sections. The outer cornified layer of the epidermis possesses properties of strength, flexibility, high electrical impedance and dryness that retards penetration and proliferation of microorganisms. The cornified protective layer is formed by the migration of maturing keratinocytes that are formed at the junction of the dermis and epidermis.
Vitamin E (tocopherol) is an essential part of skin dynamics and is known to be very important for skin health, with deficiency manifesting as a cornified, scaly delicate skin, thickened epidermis, scaling, lesions, chronic infection, inflammation and erythema. Vitamin E is the main naturally occurring lipid soluble agent protecting the skin from stress, and is the main lipid soluble agent protecting the cell membrane lipids from peroxidation.
Skin is subject to constant stress due to exposure to everyday elements—sun, wind and water. As a result, it is common for many topical personal care products such as lotions, moisturizers, shampoo and conditioners to contain vitamin E in various forms to assist in maintaining skin health. In order to assist in maintaining skin health, it is necessary for the vitamin E to reach the target area of the dermis. The most direct method of achieving this targeting is to apply a topical formulation to the affected area. However, topical application of vitamin E to the skin using current formulations has variable success due to the skin's ability to erect an impenetrable barrier to many outside elements. It is critical to provide for the penetration of vitamin E through the epidermis to the dermis.
The use of free tocopherol is avoided because it is unstable, therefore suitable derivatives must be found. In the alimentary canal, it has been found that there is lipase activity which releases free tocopherol from the esters of tocopherol, typically the acetate ester. This lipase activity enables the use of tocopheryl acetate as a nutritional source of Vitamin E.
In contrast, the surface of the skin is deficient in lipase activity unless it is infected with microorganisms that are able to digest sebaceous excretions. Thus tocopheryl acetate must first diffuse through the epidermis into the vital derma, where the cells have a very limited lipase activity which releases the Vitamin E. It is believed that topical formulations using tocopherol acetate have not been able to deliver adequate tocopherol beyond the epidermal layers, and therefore provide little benefit. Since tocopheryl acetate is a lipidic material requiring formulation with an oil in water emulsion, absorption from such a formulation is less than optimal.
The epidermis is permeable to water soluble substances, such as tocopheryl phosphate. Until now producers of formulations containing tocopheryl phosphate utilized mono-tocopheryl phosphate isolated from the mixture produced during phosphorylation. The phosphorylation has been typically achieved using phosphorous oxychloride. The product was purified because it was believed that the by-products were deleterious to the efficacy of the monotocopheryl phosphate because not all the by-products were water soluble. The perceived deleterious effects were considered significant enough to justify the cost of complicated purification processes. Typically, the purification is performed by using ethanol to extract the di-tocopheryl phosphate and free tocopherol by-products.